Pharmaceutical solids can exist in different crystal forms, such as crystalline, amorphous, or glass and also in solvated or hydrated states (Haleblian et al., 1969, 1975; Kuhnert-Brandstaetter, 1973; Sohn 2004). Polymorphism is the ability of any element or compound to crystallize as more than one distinct crystal species.
It is a well known fact that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically-important physicochemical properties, such as stability, solubility, dissolution rate, crystal habit, tableting behavior. Changes in certain of these physiochemical properties may ultimately affect the bioavailability of the drug. Furthermore, different physical forms may have different particle size, hardness and glass transition temperatures. In certain cases, this phenomenon may affect the quality and performance of the final dosage form.
Regulatory authorities desire to have all possible polymorphic forms of a new drug substance identified prior to approval of a product containing the drug. However, as is well known in the art, the existence of polymorphic forms of any given compound cannot be predicted, and there is no standard procedure for proceeding to make a previously unknown polymorphic form. Even after a polymorph has been identified, there is no possibility of predicting whether any additional forms will ever be discovered. This has been described in many recent articles, including A. Goho, Science News, Vol. 166, No. 8, pages 122-123 (August 2004).
The compound, methyl((1 S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl) carbonyl)-2-methylpropyl)carbamate (also referred to as “Compound A”),
is a drug for the treatment of hepatitis C (HCV). It was developed by Bristol-Myers Squibb and was approved in Europe on 22 Aug. 2014. Compound A is also known as daclatasvir (also referred to as daclatasvir in free base form or daclatasvir free base).
The compound A as well as pharmaceutically acceptable salts thereof, are described in U.S. Pat. Nos. 8,303,944 and 8,329,159, the disclosures of which are hereby incorporated in their entireties by reference for all purposes. This compound inhibits the HCV nonstructural protein NSSA. Recent research suggests that it targets two steps of the viral replication process, enabling rapid decline of HCV RNA.
Compound A is a chiral molecule with four stereocenters (1,1′,2,2′) in the S configuration.
Polymorphism has been observed for methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl) carbamate dihydrochloride (also referred to as “Compound B” or daclatasvir dihydrochloride).

Although two neat (wholly) crystalline dihydrochloride salts, N-1 and N-2 of compound B have been identified in screening studies (N-2 being claimed in EP2183244), it has been confirmed that the form N-2 is the thermodynamically most stable polymorph. The N-2 form of compound B remained unchanged during storage under long-term or accelerated conditions and only this form is produced by the proposed synthetic process.
Compound A is used in the treatment of hepatitis C (HCV). This disease primarily affects the liver and the infection is often asymptomatic but the chronic infection can ultimately lead to cirrhosis which in some cases may develop liver failure, liver cancer or life threatening esophageal and gastric varices. Consequently, it would be a significant contribution to the art to provide novel forms of compound A and pharmaceutically acceptable salts thereof, having advantageous properties, and methods of preparation, pharmaceutical formulations, and methods of use thereof.